EP1802277B1 - COMPOSITION LIPOSOMALE CONTENANT UN PRINCIPE ACTIF DESTINE A RELAXER LA MUSCuLATURE LISSE ET L'EMPLOI THÉRAPEUTIQUE DE CETTE COMPOSITION - Google Patents
COMPOSITION LIPOSOMALE CONTENANT UN PRINCIPE ACTIF DESTINE A RELAXER LA MUSCuLATURE LISSE ET L'EMPLOI THÉRAPEUTIQUE DE CETTE COMPOSITION Download PDFInfo
- Publication number
- EP1802277B1 EP1802277B1 EP05802312A EP05802312A EP1802277B1 EP 1802277 B1 EP1802277 B1 EP 1802277B1 EP 05802312 A EP05802312 A EP 05802312A EP 05802312 A EP05802312 A EP 05802312A EP 1802277 B1 EP1802277 B1 EP 1802277B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- liposomes
- active ingredient
- composition according
- aqueous medium
- sildenafil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
Definitions
- the present invention relates to pharmaceutical compositions based on topically administrable active substances in liposomes, which enhance the perfusion of tissues, in particular in the genital area, as well as the preparation of such compositions and their use.
- Liposomes are known as controlled release pharmaceutical agents (see eg Overview by Ulrich, Biosci Rep. 2002; 22 (2): 129-50 ), or WO 96/14083 for SOD in liposomes.
- the formulation of local anesthetics in topically applied liposomes is known in the art; z. B. describes US 4937078 Liposomes containing common sodium channel blockers such as tetracaine, lidocaine, etc.
- chemical compounds are known which promote tissue perfusion and have become known, above all, through their use as a remedy for erectile disorders and impotence (see, for example, US Pat WO 94/28902 and EP 0967214 A1 ).
- a liposomal composition based on lidocaine and a local anesthetic is disclosed for treatment Anorectal disorders can be used.
- this composition may also contain sildenafil.
- this object is achieved by providing a liposomal system for topical, in particular transdermal and / or transmucosal, administration of active substances which bring about smooth muscle relaxation, especially that of the feeding blood vessels in the genitals.
- active substances which bring about smooth muscle relaxation, especially that of the feeding blood vessels in the genitals.
- Such an effect may e.g. induced by an induced release of calcium ions.
- the invention relates to a formulation in which the active ingredient, preferably from the group of prostaglandins, adenylate cytolases, cAMP, AMP, ATP, NO synthetases, nitric oxide (NO), NO compounds, nitrates, guanylate cyclases, cGMP, GMP, GTP and phosphodiesterases, in particular sildenafil, tadalafil and vardenafil, enclosed in liposomes and / or bound to liposomes.
- the active ingredient preferably from the group of prostaglandins, adenylate cytolases, cAMP, AMP, ATP, NO synthetases, nitric oxide (NO), NO compounds, nitrates, guanylate cyclases, cGMP, GMP, GTP and phosphodiesterases, in particular sildenafil, tadalafil and vardenafil, enclosed in liposomes and
- the inventive liposomal formulation is not only a temporary drug depot in the surrounding tissue, is released from the continuous substance, but also achieved a better bioavailability and longer half-life compared to the systemic application.
- the relaxing effect on the smooth muscle cells leads to an increased circulation of the externally treated tissues, such as the genitalia, and consequently to an increased sensitivity and sensitivity in sexual activities.
- Active substances or active substances in the context of the present invention are, in particular, those substances which intervene in the cAMP or cGMP circulation and cause an increased release of calcium ions.
- these include, for example, substances such as papaverine, phentolamine, which stimulate the cAMP pathway; Nitric oxide (NO), which exerts an important transmitter function and activates a guanylate cyclase, which in turn cGMP forms; NO donors; Nitroglycerin; minoxidil, L-arginine; Linsidomine (produced in the body by NO synthetase by conversion of arginine to citrulline); molsidomine; Phosphodiesterase inhibitors, such as sildenafil or sildenafil citrate, which intervene in the cGMP pathway, with a PDE5 receptor involved; Prostaglandins such as alprostadil (PGE-1), dinoprostone (PGE-2), which interfere with the cAMP cycle.
- PGE-1 alprosta
- sildenafil As far as sildenafil is mentioned below, it also includes tadalafil, vardenafil and their acid salts, e.g. Sildenafil citrate and vardenafil-HCI 3H2O (vardenafil hydrochloride trihydrate), meaning, as far as does not result from the respective context of meaning otherwise.
- a maximum loading density can be achieved by active loading of the liposomes with active ingredients. This process can be divided into two main categories: loading of the membrane and loading of the intraliposomal aqueous phase. Active substances containing protonatable groups, for example amino groups, can be enclosed in liposomes by H + gradient-controlled loading and then retained there in the protonated state. For this type of active loading, the most important feature is the liposome membrane / liposome medium partition coefficient. It was found that the octanol / buffer partition coefficient gives good indications provides for the transmembrane diffusion of a substance and is therefore relevant for the loading with active ingredient or for the release profile.
- liposomes with different lipid composition preferably with long chain phospholipids and low cholesterol concentrations, were prepared in a suitable loading buffer, preferably in an ammonium sulfate or citric acid / sodium carbonate buffer.
- a suitable loading buffer preferably in an ammonium sulfate or citric acid / sodium carbonate buffer.
- the surrounding medium is modified, ie, exchanged or diluted, optionally neutralized or alkalized, thereby generating an H + gradient between the intraliposomal buffer and the extraliposomal medium.
- the active substance migrates into the liposomes thanks to this H + gradient, where it is protonated and remains stable in the liposomes.
- the extent of loading or loading capacity is determined primarily by the ratio of H + concentrations within and outside the liposomes.
- active substance / lipid ratios in the range of 200-400 nmol of active ingredient per ⁇ mol of lipid to achieve similar values as are known from the literature on actively loaded liposomes.
- An increase in the active ingredient concentration in the loading medium did not increase the loading capacity.
- the active loading described above is a three-step process consisting of vesicle formation, drug addition and alkalization. It was therefore a further object of the invention to establish a one-step manufacturing process using the process described in U.S. Pat WO 02/36257 revealed cross-flow module could be realized.
- a dilution buffer eg 5% glucose solution in the ammonium sulfate system or citric acid / sodium carbonate pH 9.0 - 9.5 in the citrate system.
- the loading capacity can be further increased.
- the efficiency of the process i. increase the amount of liposomal entrapped active ingredient per ml of suspension by increasing the lipid concentration either during production or during the subsequent filtration of the vesicles.
- sildenafil When sildenafil is used as the active ingredient, the ammonium sulfate / glucose solution system is preferable for active loading since sildenafil is poorly soluble or not soluble in citrate buffer.
- NH3 which is in a reversible equilibrium with ammonium sulfate in the intraliposomal aqueous medium, tends to migrate through the liposome membrane leaving an H + .
- sildenafil migrates into the liposome, absorbing the hydrogen ion H + , making it more hydrophilic and thus remaining inside the membrane. In this way, sildenafil can be efficiently loaded into liposomes. This applies similarly to the sildenafil alternatives tadalafil and vardenafil.
- lipids that can be used are, for example, phosphatidylethanotamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin, sphingomyelin, plasmalogens, glyceroglycolipids, ceramide, glycosphingolipids, neutral glycosphingolipids.
- DPPC a phospholipid having an acyl chain length of 16 carbon atoms
- DMPC 14 carbon chain length
- a second way to reduce membrane rigidity and increase fluidity is to reduce the cholesterol level in the membrane.
- DPPC DPPC
- cholesterol 55:45 mol%
- the amount of cholesterol was successively reduced to 38% and 30%, respectively, based on the total lipid content.
- drug loading There was a slight decrease in drug loading compared to results with higher cholesterol levels.
- these liposomes showed improved skin penetration properties and remained stable in the long-term test for weeks without significant loss of active ingredient.
- cholesterol-free liposomes could be produced stably and successfully loaded with active substance, so that according to the invention the cholesterol content is in a range of 0-50 mol%, based on the total lipid content.
- a third way to make liposomal membranes more flexible is to replace the fully saturated DPPC or DMPC lipids with chicken egg phosphatidylcholine (E-PC), a natural lipid mixture with unsaturated phospholipids.
- E-PC chicken egg phosphatidylcholine
- the liposomes are preferably mixed into a hydrogel which is easier to apply to the skin than a pure suspension.
- it is within the scope of the present invention to prepare and apply topically other galenic formulations for the sildenafil liposomes in particular formulations in the form of solutions, lotions, emulsions, tinctures, sprays, ointments or creams.
- Those skilled in the art are familiar with other options, as well as the pharmaceutically acceptable adjuncts and additives necessary to make the various galenic formulations.
- Carbopol 981 NF Noveon
- a hydrogel that can be used in very low concentrations, has proven useful in earlier experiments. It is approved for pharmaceutical use, relatively cheap to purchase and available in large quantities.
- the liposomes are preferably prepared by the known crossflow method ( WO 02/36257 ) using an aqueous phase suitable for the desired active ingredient, wherein optionally at least a portion of the active ingredient is introduced into this aqueous phase and enclosed in the interior of the liposomes in the course of liposome formation.
- an H + gradient between the inside and outside of the liposomes is generated, which transports both further protonatable drug from the dilution buffer quickly and efficiently in the liposomes also retains the active ingredient already included in the course of liposome formation.
- a method can be selected in which buffer-filled liposomes are produced without active ingredient in a first step and the active substance is then loaded into the liposomes active only after the liposome production via an H + gradient, as described above.
- the lipid mixture is dissolved in 96% ethanol and depending on lipid selection or lipid composition at a temperature in the range of 25 to 60 ° C, for example in the case of DPPC liposomes at a temperature of 50 to 55 ° C, with stirring.
- the buffer solutions are preferably heated to the same temperature, for example 55 ° C.
- the polar, aqueous phase (buffer) through the cross-flow module by means of a pump, e.g. a peristaltic pump is pumped, the ethanol / lipid solution is simultaneously injected under any preselectable pressure in the polar phase.
- liposomes are preferably formed in the presence of an ammonium sulfate buffer (preferably 125 mmol).
- an ammonium sulfate buffer preferably 125 mmol.
- the aqueous phase remaining outside the liposomes in this case the ammonium sulfate solution, is modified, for example diluted with dilution buffer or replaced by diafiltration through a 5% glucose solution, whereby small amphiphilic molecules such as sildenafil can be loaded into the liposomes and protonated there in turn, NH3 escapes from the liposomes.
- An aqueous 125 mM ammonium sulfate solution typically has a pH in the range of about 5-5.5.
- sildenafil is not only taken up in the liposomes in one step, but also stably retained there.
- the amount of sildenafil taken up in such a liposomal manner was also in a range from about 160 to 230 nmol of sildenafil per ⁇ mol of total lipids (DPPC + cholesterol), depending on the pH or H + gradient.
- liposome-incorporated prostaglandin E1 was also prepared under similar process conditions. For application effects see example 2.
- a formulation of 0.5 mg of the respective substance (calculated as salt-free active ingredient) in liposomes per 1 ml hydrogel Carbopol 981 NF was selected and by volunteers in an application amount of 0.5 - 1.5 ml used per application, where sildenafil and vardenafil were each used in the form of their acid salts (sildenafil citrate or vardenafil hydrochloride trihydrate).
- the gel was applied by male volunteers by external application to the penis, by female subjects by external vaginal and / or clitoral application.
- vaginal / clitoral application of the liposomal active ingredient gel begins the effect that causes increased blood flow, thereby a pleasant, warm feeling is created and as a result increased production of vaginal secretions has been noted.
- the subjects reported slight contractions of the vaginal musculature (similar to orgasm), increased sexual sensation during intercourse, and a greater sense of orgasm.
- the liposomal active substance preparations according to the invention in any case appear to be clearly effective in external use, even in women. They can therefore also be used for the therapeutic treatment of female sexual dysfunction (female sexual dysfunction, FSD), such as for the treatment of female sexual arousal disorder (FSAD).
- FSD female sexual dysfunction
- FSAD female sexual arousal disorder
- prostaglandin E1 in liposomes For example, prostaglandin E1 in liposomes
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
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- General Chemical & Material Sciences (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
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- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (15)
- Composition pharmaceutique pour application topique, avec une principe actif, inclus dans des liposomes, exerçant, directement ou indirectement, un effet relaxant sur la musculature lisse, caractérisée en ce que les liposomes comprennent une proportion molaire de cholestérol dans la fourchette de 0 à 50 %, de préférence de 30 à 45 %, par rapport à la quantité globale de lipides, ainsi que, intérieurement, présentent un milieu aqueux ayant une valeur de pH dans la fourchette de 2,5 à 5,5 et, dans celui-ci, au moins un principe actif protoné, issu du groupe de la prostaglandine, des adénylatcyclases, cAMP, AMP, ATP, NO-synthétases, monoxyde d'azote (NO), combinaisons NO, nitrates, guanylate-cyclases, cGMP, GMP, GTP et phosphodiestérases, en une concentration d'au moins 100 nmoles par µmole de lipide, et où un milieu aqueux à valeur de pH neutre ou alcaline est présent à l'extérieur des liposomes.
- Composition selon la revendication 1, caractérisée en ce que, à l'intérieur des liposomes, est présent un milieu aqueux à valeur de pH dans la fourchette de 5,0 à 5,5 et, à l'extérieur des liposomes, est présent un milieu aqueux à valeur de pH dans la fourchette de 7 à 8.
- Composition selon la revendication 1 ou 2, caractérisée en ce que le principe actif est sélectionné dans le groupe des sildénafil, tadalafil et vardénafil, ainsi que leurs sels acides.
- Composition selon la revendication 3, caractérisée en ce que le principe actif est du sildénafil citrate et le milieu aqueux à l'intérieur des liposomes est un système tampon au sulfate d'ammonium.
- Composition selon l'une des revendications 1 à 4, caractérisée en ce que le milieu aqueux à l'intérieur des liposomes est un système tampon au sulfate d'ammonium et le milieu à l'extérieur des liposomes est une solution de glucose à 5 %.
- Composition selon l'une des revendications 1 à 3, caractérisée en ce que le milieu aqueux à l'intérieur des liposomes est un système tampon au citrate et le milieu à l'extérieur des liposomes est une tampon acide citrique/carbonate de sodium.
- Composition selon l'une des revendications 1 à 6, caractérisée en ce que les liposomes contiennent des phospholipides ayant une longueur de la chaîne acyl d'au moins 14, de préférence d'au moins 16, atomes de carbone.
- Composition selon l'une des revendications 1 à 7, caractérisée en ce que les liposomes présentent une taille moyenne dans la fourchette de 150 à 500 nm et contiennent le principe actif en une concentration dans la fourchette de 150 à 400 nmoles par µmole de lipide.
- Composition selon l'une des revendications 1 à 8, caractérisée en ce qu'elle se présente sous forme de suspension, lotion, émulsion, teinture, spray, gel, crème ou onguent, de préférence sous forme aseptique.
- Procédé de préparation d'une composition pharmaceutique définie aux revendications 1 à 19, caractérisé en ce que des liposomes spontanés, avec un milieu aqueux à l'intérieur de ceux-ci, sont produits par injection d'une phase lipide éthanolique ayant une proportion molaire de cholestérol de 0 à 50 %, de préférence de 30 à 45 %, rapportée à la quantité globale de lipide, dans une phase aqueuse ayant une valeur de pH dans la fourchette de 2,5 à 5,5, suite à quoi la phase aqueuse est modifiée, précisément diluée, soumise à échange, neutralisée ou alkalisée, de manière qu'un gradient H+ se constitue entre les côtés intérieur et extérieur des liposomes, et où un principe actif protonable, issu du groupe de la prostaglandine, des adénylatcyclases, cAMP, AMP, ATP, NO-synthétases, monoxyde d'azote (NO), combinaisons NO, nitrates, guanylate-cyclases, cGMP, GMP, GTP et phosphodiestérases,a) se présente dans la phase aqueuse et est absorbé au cours de la formation, s'effectuant spontanément, des liposomes, et/oub) ensuite, une fois effectuée la formation de vésicules, est ajouté à la phase aqueuse modifiée et migre, le long du gradient H+, dans les liposomes,dont le resultat et la formation de liposomes qui contiennent le principe actif en une concentration d'au moins 100, en particulier dans la fourchette de 150 à 400 nmoles par µmole de lipide.
- Procédé selon la revendication 10, caractérisé en ce que la modification de la phase aqueuse est effectuée directement après avoir effectue la formation des liposomes, par dilution avec un tampon neutre ou alcalin, faisant qu'une valeur de pH de 7 à 8 est atteinte.
- Procédé selon la, revendication 11, caractérisé en ce que, avant la modification, la phase aqueuse présente une valeur de pH de 3,5 à 4,5 et contient du sulfate d'ammonium, et la modification est effectuée par dilution de la phase aqueuse avec une solution de glucose à 5 %.
- Procédé selon l'une des revendications 10 à 12, caractérisé en ce que la composition pharmaceutique est préparée sous forme de suspension, lotion, émulsion, teinture, spray, gel, crème ou onguent, de préférence sous forme aseptique.
- Composition pharmaceutique selon l'une des revendications 1 à 9, pour utilisation en tant que médicament, pour applications externes, en particulier topiques, transdermales et/ou par voie transmuqueuse, dans la zone génitale.
- Composition pharmaceutique selon la revendication 14, pour utilisation dans la prophylaxie et/ou la thérapie des troubles érectiles chez l'homme, dans le traitement des troubles sexuels de la femme, en particulier dans la thérapie des désordres de l'excitation féminine (FSAD, female sexual arousal disorder - désordre sexuel femelle d'éveil), ou pour l'augmentation de la sensation de plaisir sexuelle.
Priority Applications (3)
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SI200530965T SI1802277T1 (sl) | 2004-10-18 | 2005-10-14 | Liposomalni sestavek ki vsebuje učinkovino za relaksiranje gladke muskulature priprava tega sestavka in njegova terapevtska uporaba |
EP05802312A EP1802277B1 (fr) | 2004-10-18 | 2005-10-14 | COMPOSITION LIPOSOMALE CONTENANT UN PRINCIPE ACTIF DESTINE A RELAXER LA MUSCuLATURE LISSE ET L'EMPLOI THÉRAPEUTIQUE DE CETTE COMPOSITION |
PL05802312T PL1802277T3 (pl) | 2004-10-18 | 2005-10-14 | Kompozycja liposomowa zawierająca aktywny składnik do rozluźniania mięśni gładkich, otrzymywania tej kompozycji i jej zastosowanie terapeutyczne |
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EP04024753 | 2004-10-18 | ||
PCT/EP2005/011054 WO2006042701A1 (fr) | 2004-10-18 | 2005-10-14 | Composition liposomale contenant un principe actif destine a relaxer la musculature lisse, utilisation de cette composition et son utilisation therapeutique |
EP05802312A EP1802277B1 (fr) | 2004-10-18 | 2005-10-14 | COMPOSITION LIPOSOMALE CONTENANT UN PRINCIPE ACTIF DESTINE A RELAXER LA MUSCuLATURE LISSE ET L'EMPLOI THÉRAPEUTIQUE DE CETTE COMPOSITION |
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EP (1) | EP1802277B1 (fr) |
JP (1) | JP5688199B2 (fr) |
KR (1) | KR101289917B1 (fr) |
CN (1) | CN101043874A (fr) |
AT (1) | ATE454884T1 (fr) |
AU (1) | AU2005296719B2 (fr) |
CA (1) | CA2583332C (fr) |
DE (1) | DE502005008880D1 (fr) |
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PT (1) | PT1802277E (fr) |
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US20040018237A1 (en) | 2002-05-31 | 2004-01-29 | Perricone Nicholas V. | Topical drug delivery using phosphatidylcholine |
CN101269212B (zh) * | 2008-04-30 | 2013-09-18 | 上海麟翔生物技术有限公司 | 一种可吞咽的漱口液 |
DE102009031274A1 (de) * | 2009-06-30 | 2011-01-13 | Justus-Liebig-Universität Giessen | Liposomen zur pulmonalen Applikation |
LT2523669T (lt) * | 2010-01-11 | 2017-04-25 | Inotek Pharmaceuticals Corporation | Akispūdžio mažinimo būdas, derinys ir rinkinys |
EP2556820A4 (fr) * | 2010-04-05 | 2015-01-21 | Sk Chemicals Co Ltd | Composition contenant un inhibiteur de pde5 pour l'atténuation des rides de la peau |
CO6280050A1 (es) * | 2010-06-08 | 2011-05-20 | Sante S A Lab | Forma farmaceutica de inhibidores de la fosfodiesterasa para administracion transmucosa |
RU2482847C2 (ru) * | 2010-11-17 | 2013-05-27 | Леонид Леонидович Клопотенко | Фармацевтическая композиция, содержащая силденафил или алпростадил, миноксидил или эуфиллин, тестостерон или йохимбин и липосомы для местного применения |
WO2012094033A1 (fr) * | 2011-01-05 | 2012-07-12 | Livon Laboratories | Procédés de fabrication de liposomes, compositions à base de liposomes préparées en utilisant les procédés, et procédés d'utilisation associés |
EP2685962A1 (fr) | 2011-03-17 | 2014-01-22 | Transdermal Biotechnology, Inc. | Systèmes topiques d'oxyde nitrique et leurs procédés d'utilisation |
RU2618462C2 (ru) * | 2011-12-26 | 2017-05-03 | Тритек Биофармасьютикалз Ко., Лтд. | Способ и улучшенная фармацевтическая композиция для ускорения трансдермальной доставки ингибитора pde-5 |
US9445993B2 (en) * | 2012-04-16 | 2016-09-20 | Rutgers, The State University Of New Jersey | Nanotechnology approach for inhalation therapies |
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- 2005-10-14 AT AT05802312T patent/ATE454884T1/de active
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DE502005008880D1 (de) | 2010-03-04 |
EA200700892A1 (ru) | 2007-08-31 |
KR101289917B1 (ko) | 2013-07-25 |
CA2583332A1 (fr) | 2006-04-27 |
PL1802277T3 (pl) | 2010-07-30 |
SI1802277T1 (sl) | 2010-05-31 |
US20090324698A1 (en) | 2009-12-31 |
ATE454884T1 (de) | 2010-01-15 |
AU2005296719B2 (en) | 2011-02-03 |
JP2008516911A (ja) | 2008-05-22 |
CA2583332C (fr) | 2013-10-01 |
EP1802277A1 (fr) | 2007-07-04 |
DK1802277T3 (da) | 2010-05-17 |
KR20070069164A (ko) | 2007-07-02 |
WO2006042701A1 (fr) | 2006-04-27 |
PT1802277E (pt) | 2010-04-01 |
NZ554183A (en) | 2009-04-30 |
AU2005296719A1 (en) | 2006-04-27 |
CN101043874A (zh) | 2007-09-26 |
ES2339577T3 (es) | 2010-05-21 |
JP5688199B2 (ja) | 2015-03-25 |
EA011391B1 (ru) | 2009-02-27 |
US8524274B2 (en) | 2013-09-03 |
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